2.1 Recommended Dosage in Adult Patients

The recommended oral dosage of etravirine tablets for adult patients is 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following a meal. The type of food does not affect the exposure to etravirine [see Clinical Pharmacology (12.3)].

2.2 Recommended Dosage During Pregnancy

The recommended oral dosage of etravirine tablets for pregnant individuals is 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following a meal [see Use in Specific Populations (8.1)].

2.3 Recommended Dosage in Pediatric Patients (6 Years to Less Than 18 Years of Age)

The recommended dosage of etravirine tablets for pediatric patients 6 years to less than 18 years of age and weighing at least 16 kg is based on body weight (see Table 1) not exceeding the recommended adult dosage. Etravirine tablets should be taken orally, following a meal. The type of food does not affect the exposure to etravirine tablets [see Clinical Pharmacology (12.3)].

Table 1: Recommended Dosage of Etravirine Tablets for Pediatric Patients 6 Years to Less Than 18 Years of Age

Additional pediatric use information is approved for Janssen Products, LP’s INTELENCE® (etravirine) tablets. However, due to Janssen Products, LP’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2.4 Method of Administration

Instruct patients to swallow the etravirine tablet(s) whole with liquid such as water. Patients who are unable to swallow the etravirine tablet(s) whole may disperse the tablet(s) in water. Instruct the patient to do the following:

• place the tablet(s) in 5 mL (1 teaspoon) of water, or at least enough liquid to cover the medication,
• stir well until the water looks milky,
• add approximately 15 mL (1 tablespoon) of liquid. Water may be used but other liquids, such as orange juice or milk, may improve taste. Patients should not place the tablets in orange juice or milk without first adding water. The use of warm (temperature greater than 104°F [greater than 40°C]) or carbonated beverages should be avoided.
• drink the mixture immediately,
• rinse the glass several times with orange juice, milk or water and completely swallow the rinse each time to make sure the patient takes the entire dose.

5.1 Severe Skin and Hypersensitivity Reactions

Severe, potentially life-threatening and fatal skin reactions have been reported. In clinical trials, these include cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme. Hypersensitivity reactions including Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have also been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. In Phase 3 clinical trials, Grade 3 and 4 rashes were reported in 1.3% of subjects receiving etravirine compared to 0.2% of placebo subjects. A total of 2.2% of HIV-1-infected subjects receiving etravirine discontinued from Phase 3 trials due to rash [see Adverse Reactions (6.1)]. Rash occurred most commonly during the first 6 weeks of therapy. The incidence of rash was higher in females [see Adverse Reactions (6.1)]. Stevens-Johnson syndrome was reported in 1.1% (2/177) of pediatric patients less than 18 years of age receiving etravirine in combination with other HIV-1 antiretroviral agents in an observational study.

Discontinue etravirine immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema). Clinical status including liver transaminases should be monitored and appropriate therapy initiated. Delay in stopping etravirine treatment after the onset of severe rash may result in a life-threatening reaction.

5.2 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

The concomitant use of etravirine and other drugs may result in potentially significant drug interactions, some of which may lead to [see Drug Interactions (7.3)]:

• Loss of therapeutic effect of concomitant drug or etravirine and possible development of resistance.
• Possible clinically significant adverse reactions from greater exposures of etravirine or other concomitant drugs.

See Table 4 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during etravirine therapy and review concomitant medications during etravirine therapy.

5.3 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including etravirine. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP) or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.4 Fat Redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials Experience in Adults

The safety assessment is based on all data from 1,203 subjects in the Phase 3 placebo-controlled trials, TMC125-C206 and TMC125-C216, conducted in antiretroviral treatment-experienced HIV-1-infected adult subjects, 599 of whom received etravirine (200 mg twice daily). In these pooled trials, the median exposure for subjects in the etravirine arm and placebo arm was 52.3 and 51.0 weeks, respectively. Discontinuations due to adverse drug reactions (ADRs) were 5.2% in the etravirine arm and 2.6% in the placebo arm.

The most frequently reported ADR at least Grade 2 in severity was rash (10.0%). Stevens-Johnson syndrome, drug hypersensitivity reaction and erythema multiforme were reported in less than 0.1% of subjects during clinical development with etravirine [see Warnings and Precautions (5.1)]. A total of 2.2% of HIV-1-infected subjects in Phase 3 trials receiving etravirine discontinued due to rash. In general, in clinical trials, rash was mild to moderate, occurred primarily in the second week of therapy, and was infrequent after Week 4. Rash generally resolved within 1 to 2 weeks on continued therapy. The incidence of rash was higher in women compared to men in the etravirine arm in the Phase 3 trials (rash ≥ Grade 2 was reported in 9/60 [15.0%] women versus 51/539 [9.5%] men; discontinuations due to rash were reported in 3/60 [5.0%] women versus 10/539 [1.9%] men) [see Warnings and Precautions (5.1)]. Patients with a history of NNRTI-related rash did not appear to be at increased risk for the development of etravirine-related rash compared to patients without a history of NNRTI-related rash.

Common Adverse Reactions

Clinical ADRs of moderate intensity or greater (greater than or equal to Grade 2) and reported in at least 2% of subjects treated with etravirine and occurring at a higher rate compared to placebo (excess of 1%) are presented in Table 2. Laboratory abnormalities considered ADRs are included in Table 3.

Table 2: Adverse Drug Reactions (Grades 2 to 4) in at Least 2% of Adult Subjects (Pooled TMC125-C206 and TMC125-C216 Trials)

Less Common Adverse Reactions

Treatment-emergent ADRs occurring in less than 2% of subjects (599 subjects) receiving etravirine and of at least moderate intensity (greater than or equal to Grade 2) are listed below by body system:

Cardiac Disorders: myocardial infarction, angina pectoris, atrial fibrillation

Ear and Labyrinth Disorders: vertigo

Eye Disorders: blurred vision

Gastrointestinal Disorders: gastroesophageal reflux disease, flatulence, gastritis, abdominal distension, pancreatitis, constipation, dry mouth, hematemesis, retching, stomatitis

General Disorders and Administration Site Conditions: sluggishness

Hematologic Disorders: hemolytic anemia

Hepatobiliary Disorders: hepatic failure, hepatomegaly, cytolytic hepatitis, hepatic steatosis, hepatitis

Immune System Disorders: drug hypersensitivity, immune reconstitution syndrome

Metabolism and Nutrition Disorders: diabetes mellitus, anorexia, dyslipidemia

Nervous System Disorders: paresthesia, somnolence, convulsion, hypoesthesia, amnesia, syncope, disturbance in attention, hypersomnia, tremor

Psychiatric Disorders: anxiety, sleep disorders, abnormal dreams, confusional state, disorientation, nervousness, nightmares

Renal and Urinary Disorders: acute renal failure

Reproductive System and Breast Disorders: gynecomastia

Respiratory, Thoracic and Mediastinal Disorders: exertional dyspnea, bronchospasm

Skin and Subcutaneous Tissue Disorders: night sweats, lipohypertrophy, prurigo, hyperhidrosis, dry skin, swelling face

Additional ADRs of at least moderate intensity observed in other trials were acquired lipodystrophy, angioneurotic edema, erythema multiforme and hemorrhagic stroke, each reported in no more than 0.5% of subjects.

Laboratory Abnormalities in Treatment-Experienced Patients

Selected Grade 2 to Grade 4 laboratory abnormalities that represent a worsening from baseline observed in adult subjects treated with etravirine are presented in Table 3.

Table 3: Selected Grade 2 to 4 Laboratory Abnormalities Observed in Treatment-Experienced Subjects (Pooled TMC125-C206 and TMC125-C216 Trials)

Patients Co-Infected With Hepatitis B and/or Hepatitis C Virus

In Phase 3 trials TMC125-C206 and TMC125-C216, 139 subjects (12.3%) with chronic hepatitis B and/or hepatitis C virus co-infection out of 1,129 subjects were permitted to enroll. AST and ALT abnormalities occurred more frequently in hepatitis B and/or hepatitis C virus co-infected subjects for both treatment groups. Grade 2 or higher laboratory abnormalities that represent a worsening from baseline of AST, ALT or total bilirubin occurred in 27.8%, 25.0% and 7.1% respectively, of etravirine-treated co-infected subjects as compared to 6.7%, 7.5% and 1.8% of non-co-infected etravirine-treated subjects. In general, adverse events reported by etravirine-treated subjects with hepatitis B and/or hepatitis C virus co-infection were similar to etravirine-treated subjects without hepatitis B and/or hepatitis C virus co-infection.

Clinical Trials Experience in Pediatric Subjects (6 Years to Less Than 18 years of age)

The safety assessment in pediatric subjects is based on a single-arm trial. TMC125-C213 is a Phase 2 trial in which 101 antiretroviral treatment-experienced HIV-1 infected pediatric subjects 6 years to less than 18 years of age received etravirine in combination with other antiretroviral agents (Week 24 analysis) [see Clinical Studies (14.2)].

In TMC125-C213, the frequency, type and severity of adverse drug reactions in pediatric subjects 6 years to less than 18 years of age were comparable to those observed in adult subjects, except for rash which was observed more frequently in pediatric subjects. The most common adverse drug reactions in at least 2% of pediatric subjects were rash and diarrhea. Rash was reported more frequently in female subjects than in male subjects (rash ≥ Grade 2 was reported in 13/64 [20.3%] females versus 2/37 [5.4%] males; discontinuations due to rash were reported in 4/64 [6.3%] females versus 0/37 [0%] males). Rash (greater than or equal to Grade 2) occurred in 15% of pediatric subjects from 6 years to less than 18 years of age. In the majority of cases, rash was mild to moderate, of macular/papular type, and occurred in the second week of therapy. Rash was self-limiting and generally resolved within 1 week on continued therapy. The safety profile for subjects who completed 48 weeks of treatment was similar to the safety profile for subjects who completed 24 weeks of treatment.

Additional pediatric use information is approved for Janssen Products, LP’s INTELENCE® (etravirine) tablets. However, due to Janssen Products, LP’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

6.2 Postmarketing Experience

The following events have been identified during postmarketing use of etravirine. Because these events are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: Severe hypersensitivity reactions including DRESS and cases of hepatic failure have been reported [see Warnings and Precautions (5.1)].

Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis

Skin and Subcutaneous Tissue Disorders: Fatal cases of toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported [see Warnings and Precautions (5.1)].

7.1 Potential for Other Drugs to Affect Etravirine

Etravirine is a substrate of CYP3A, CYP2C9, and CYP2C19. Therefore, co-administration of etravirine with drugs that induce or inhibit CYP3A, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of etravirine (see Table 4) [see Clinical Pharmacology (12.3)].

7.2 Potential for Etravirine to Affect Other Drugs

Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P-glycoprotein (P-gp). Therefore, co-administration of drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-gp with etravirine may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s) (see Table 4) [see Clinical Pharmacology (12.3)].

7.3 Significant Drug Interactions

Table 4 shows significant drug interactions based on which, alterations in dose or regimen of etravirine and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with etravirine are also included in Table 4 [see Clinical Pharmacology (12.3)].

Table 4: Significant Drug Interactions

7.4 Drugs Without Clinically Significant Interactions with Etravirine

In addition to the drugs included in Table 4, the interaction between etravirine and the following drugs were evaluated in clinical studies and no dose adjustment is needed for either drug [see Clinical Pharmacology (12.3)]: didanosine, enfuvirtide (ENF), ethinylestradiol/norethindrone, omeprazole, paroxetine, raltegravir, ranitidine, and tenofovir disoproxil fumarate.

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to etravirine during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

Prospective pregnancy data from clinical trials and the APR are not sufficient to adequately assess the risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Etravirine use during pregnancy has been evaluated in a limited number of individuals as reported by the APR, and available data show 1 birth defect in 66 first trimester exposures to etravirine-containing regimens (see Data).

The estimated background rate for major birth defects is 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk of major birth defects and miscarriage for the indicated population is unknown.

In animal reproduction studies, no adverse developmental effects were observed with orally administered etravirine at exposures equivalent to those at the maximum recommended human dose (MRHD) of 400 mg daily (see Data).

Data

Human Data

Based on prospective reports to the APR of 116 live births following exposure to etravirine-containing regimens during pregnancy (including 66 exposed in the first trimester and 38 exposed in the second/third trimester), the number of birth defects in live births for etravirine was 1 out of 66 with first trimester exposure and 0 out of 38 with second/third trimester exposure. Prospective reports from the APR of overall major birth defects in pregnancies exposed to etravirine are compared with a U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease; these limitations preclude an accurate comparison of outcomes.

Etravirine (200 mg twice daily) in combination with other antiretroviral agents was evaluated in a clinical trial enrolling 15 pregnant subjects during the second and third trimesters of pregnancy and postpartum. Thirteen subjects completed the trial through postpartum period (6 to 12 weeks after delivery). The pharmacokinetic data demonstrated that exposure to total etravirine was generally higher during pregnancy compared with postpartum [see Clinical Pharmacology (12.3)].

Among subjects who were virologically suppressed (HIV-1 RNA less than 50 copies/mL) at baseline (9/13), virologic suppression was maintained through the third trimester and postpartum period. Among subjects with HIV-1 RNA greater than 50 copies/mL and less than 400 copies/mL at baseline (3/13), viral loads remained less than 400 copies/mL. In one subject with HIV-1 RNA greater than 1,000 copies/mL at baseline (1/13), HIV-1 RNA remained greater than 1,000 copies/mL during the study period. Thirteen infants were born to 13 HIV-infected pregnant individuals in this study. HIV-1 test results were not available for 2 infants. Among the eleven infants with HIV-1 test results available, who were born to 11 HIV-infected pregnant individuals who completed the study, all had test results that were negative for HIV-1 at the time of delivery. No unexpected safety findings were observed compared with the known safety profile of etravirine in non-pregnant adults.

Animal Data

Reproductive and developmental toxicity studies were performed in rats (at 250, 500 and 1,000 mg/kg/day) and rabbits (at 125, 250 and 375 mg/kg/day) administered etravirine on gestation days 6 through 16, and 6 through 19, respectively. In both species, no treatment-related embryo-fetal effects were observed. In addition, no treatment-related effects were observed in a pre- and postnatal development study performed in rats administered oral doses up to 500 mg/kg/day on gestation days 7 through lactation day 7. The systemic drug exposures achieved at the high dose in these animal studies were equivalent to those at the MRHD.

8.2 Lactation

Risk Summary

The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.

Based on limited data, etravirine has been shown to be present in human breast milk. There are no data on the effects of etravirine on the breastfed infant, or the effects of etravirine on milk production.

Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants) and (3) adverse reactions in breastfed infants similar to those seen in adults, instruct mothers not to breastfeed if they are receiving etravirine.

8.4 Pediatric Use

The safety and effectiveness of etravirine have been established for the treatment of HIV-infected pediatric patients from 6 years of age to less than 18 years [see Indications and Usage (1) and Dosage and Administration (2.3)]. Use of etravirine in pediatric patients 6 years to less than 18 years of age is supported by evidence from adequate and well-controlled studies of etravirine in adults with additional data from a Phase 2 trial in treatment-experienced pediatric subjects, TMC125-C213, 6 years to less than 18 years of age (N=101). The study was an open-label, single arm trial of etravirine plus an optimized background regimen. In the clinical trial, the safety, pharmacokinetics, and efficacy were comparable to that observed in adults except for rash (greater than or equal to Grade 2) which was observed more frequently in pediatric subjects [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)]. Postmarketing reports of Stevens-Johnson syndrome in pediatric patients receiving etravirine have been reported [see Warnings and Precautions (5.1), and Adverse Reactions (6.2)].

Treatment with etravirine is not recommended in pediatric patients less than 2 years of age [see Clinical Pharmacology (12.3)].

Additional pediatric use information is approved for Janssen Products, LP’s INTELENCE® (etravirine) tablets. However, due to Janssen Products, LP’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

8.5 Geriatric Use

Clinical studies of etravirine did not include sufficient numbers of subjects aged 65 years of age and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

No dose adjustment of etravirine is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. The pharmacokinetics of etravirine have not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment

Since the renal clearance of etravirine is negligible (less than 1.2%), a decrease in total body clearance is not expected in patients with renal impairment. No dose adjustments are required in patients with renal impairment. As etravirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Etravirine is an antiretroviral drug [see Microbiology (12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology

In a thorough QT/QTc study in 41 healthy subjects, etravirine 200 mg twice daily or 400 mg once daily did not affect the QT/QTc interval.

12.3 Pharmacokinetics

The pharmacokinetic properties of etravirine were determined in healthy adult subjects and in treatment-experienced HIV-1-infected adult and pediatric subjects. The systemic exposures (AUC) to etravirine were lower in HIV-1-infected subjects (Table 5) than in healthy subjects.

Table 5: Population Pharmacokinetic Estimates of Etravirine 200 mg Twice Daily in HIV-1-Infected Adult Subjects (Integrated Data from Phase 3 Trials at Week 48)*

Note: The median protein binding adjusted EC50 for MT4 cells infected with HIV-1/IIIB in vitro equals 4 ng/mL.

Absorption and Bioavailability

Following oral administration, etravirine was absorbed with a Tmax of about 2.5 to 4 hours. The absolute oral bioavailability of etravirine is unknown.

In healthy subjects, the absorption of etravirine is not affected by co-administration of oral ranitidine or omeprazole, drugs that increase gastric pH.

Effects of Food on Oral Absorption

The systemic exposure (AUC) to etravirine was decreased by about 50% when etravirine tablet was administered under fasting conditions, as compared to when etravirine tablet was administered following a meal. Within the range of meals studied, the systemic exposures to etravirine were similar. The total caloric content of the various meals evaluated ranged from 345 kilocalories (17 grams fat) to 1,160 kilocalories (70 grams fat).

Distribution

Etravirine is about 99.9% bound to plasma proteins, primarily to albumin (99.6%) and alpha 1-acid glycoprotein (97.66% to 99.02%) in vitro. The distribution of etravirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.

Metabolism

In vitro experiments with human liver microsomes (HLMs) indicate that etravirine primarily undergoes metabolism by CYP3A, CYP2C9, and CYP2C19 enzymes. The major metabolites, formed by methyl hydroxylation of the dimethylbenzonitrile moiety, were at least 90% less active than etravirine against wild-type HIV in cell culture.

Elimination

After single dose oral administration of 800 mg 14C-etravirine, 93.7% and 1.2% of the administered dose of 14C-etravirine was recovered in the feces and urine, respectively. Unchanged etravirine accounted for 81.2% to 86.4% of the administered dose in feces. Unchanged etravirine was not detected in urine. The mean (± standard deviation) terminal elimination half-life of etravirine was about 41 (± 20) hours.

Specific Populations

Geriatric Patients

Population pharmacokinetic analysis in HIV-infected subjects showed that etravirine pharmacokinetics are not considerably different within the age range (18 to 77 years) evaluated [see Use in Specific Populations (8.5)].

Pediatric Patients

The pharmacokinetics of etravirine in 101 treatment-experienced HIV-1-infected pediatric subjects, 6 years to less than 18 years of age showed that the administered weight-based dosages resulted in etravirine exposure comparable to that in adults receiving etravirine 200 mg twice daily [see Dosage and Administration (2.3)]. The pharmacokinetic parameters for etravirine (AUC12h and C0h) are summarized in Table 6.

Table 6: Pharmacokinetic Parameters for Etravirine in Treatment-Experienced HIV-1-Infected Pediatric Subjects 6 Years to Less Than 18 Years of Age (TMC125-C213 [Population PK])

The pharmacokinetics and dose of etravirine in pediatric subjects less than 2 years of age have not been established [see Use in Specific Populations (8.4)].

Additional pediatric use information is approved for Janssen Products, LP’s INTELENCE® (etravirine) tablets. However, due to Janssen Products, LP’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Male and Female Patients

No significant pharmacokinetic differences have been observed between males and females.

Racial or Ethnic Groups

Population pharmacokinetic analysis of etravirine in HIV-infected subjects did not show an effect of race on exposure to etravirine.

Patients with Renal Impairment

The pharmacokinetics of etravirine have not been studied in patients with renal impairment. The results from a mass balance study with 14C-etravirine showed that less than 1.2% of the administered dose of etravirine is excreted in the urine as metabolites. No unchanged drug was detected in the urine. As etravirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis [see Use in Specific Populations (8.7)].

Patients with Hepatic Impairment

Etravirine is primarily metabolized by the liver. The steady-state pharmacokinetic parameters of etravirine were similar after multiple dose administration of etravirine to subjects with normal hepatic function (16 subjects), mild hepatic impairment (Child-Pugh Class A, 8 subjects), and moderate hepatic impairment (Child-Pugh Class B, 8 subjects). The effect of severe hepatic impairment on the pharmacokinetics of etravirine has not been evaluated [see Use in Specific Populations (8.6)].

Pregnancy and Postpartum

After intake of etravirine 200 mg twice daily in combination with other antiretroviral agents (13 subjects with 2 NRTIs, 1 subject with 2 NRTIs + lopinavir + ritonavir, 1 subject with 2 NRTIs + raltegravir), based on intra-individual comparison, the Cmax and AUC12h of total etravirine were 23% to 42% higher during pregnancy compared with postpartum (6 to 12 weeks). The Cmin of total etravirine was 78 to 125% higher during pregnancy compared with postpartum (6 to 12 weeks), while two subjects had Cmin < 10 ng/mL in the postpartum period (6 to 12 weeks) [Cmin of total etravirine was 11% to 16% higher when these 2 subjects are excluded] (see Table 7) [see Use in Specific Populations (8.1)]. Increased etravirine exposures during pregnancy are not considered clinically significant. The protein binding of etravirine was similar (> 99%) during the second trimester, third trimester, and postpartum period.

Table 7: Pharmacokinetic Results of Total Etravirine After Administration of Etravirine 200 mg Twice Daily as Part of an Antiretroviral Regimen, During the 2nd Trimester of Pregnancy, the 3rd Trimester of Pregnancy, and Postpartum.

Patients with Hepatitis B and/or Hepatitis C Virus Co-Infection

Population pharmacokinetic analysis of the TMC125-C206 and TMC125-C216 trials showed reduced clearance for etravirine in HIV-1-infected subjects with hepatitis B and/or C virus co-infection. Based upon the safety profile of etravirine [see Adverse Reactions (6)], no dose adjustment is necessary in patients co-infected with hepatitis B and/or C virus.

Drug Interactions

Etravirine is a substrate of CYP3A, CYP2C9, and CYP2C19. Therefore, co-administration of etravirine with drugs that induce or inhibit CYP3A, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of etravirine.

Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P-gp. Therefore, co-administration of drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-gp with etravirine may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s).

Drug interaction studies were performed with etravirine and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of other drugs on the AUC, Cmax, and Cmin values of etravirine are summarized in Table 8 (effect of other drugs on etravirine). The effect of co-administration of etravirine on the AUC, Cmax, and Cmin values of other drugs are summarized in Table 9 (effect of etravirine on other drugs). For information regarding clinical recommendations, [see Drug Interactions (7)].

Table 8: Drug Interactions: Pharmacokinetic Parameters for Etravirine in the Presence of Co-administered Drugs

Table 9: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Etravirine

12.4 Microbiology

Mechanism of Action

Etravirine is an NNRTI of HIV-1. Etravirine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. Etravirine does not inhibit the human DNA polymerases α, β, and γ.

Antiviral Activity in Cell Culture

Etravirine exhibited activity against laboratory strains and clinical isolates of wild-type HIV-1 in acutely infected T-cell lines, human peripheral blood mononuclear cells, and human monocytes/macrophages with median EC50 values ranging from 0.9 nM to 5.5 nM (i.e. 0.4 ng/mL to 2.4 ng/mL). Etravirine demonstrated antiviral activity in cell culture against a broad panel of HIV-1 group M isolates (subtype A, B, C, D, E, F, G) with EC50 values ranging from 0.29 nM to 1.65 nM and EC50 values ranging from 11.5 nM to 21.7 nM against group O primary isolates. Etravirine did not show antagonism when studied in combination with the following antiretroviral drugs—the NNRTIs delavirdine, efavirenz, and nevirapine; the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine; the PIs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir; the gp41 fusion inhibitor ENF; the integrase strand transfer inhibitor raltegravir and the CCR5 co-receptor antagonist maraviroc.

Resistance

In Cell Culture

Etravirine-resistant strains were selected in cell culture originating from wild-type HIV-1 of different origins and subtypes, as well as NNRTI resistant HIV-1. Development of reduced susceptibility to etravirine typically required more than one substitution in reverse transcriptase of which the following were observed most frequently: L100I, E138K, E138G, V179I, Y181C, and M230I.

In Treatment-Experienced Subjects

In the Phase 3 trials TMC125-C206 and TMC125-C216, substitutions that developed most commonly in subjects with virologic failure at Week 48 to the etravirine-containing regimen were V179F, V179I, and Y181C which usually emerged in a background of multiple other NNRTI resistance-associated substitutions. In all the trials conducted with etravirine in HIV-1 infected subjects, the following substitutions emerged most commonly: L100I, E138G, V179F, V179I, Y181C and H221Y. Other NNRTI-resistance-associated substitutions which emerged on etravirine treatment in less than 10% of the virologic failure isolates included K101E/H/P, K103N/R, V106I/M, V108I, Y181I, Y188L, V189I, G190S/C, N348I and R356K. The emergence of NNRTI substitutions on etravirine treatment contributed to decreased susceptibility to etravirine with a median fold-change in etravirine susceptibility of 40-fold from reference and a median fold-change of 6-fold from baseline.

Cross-Resistance

Cross-resistance among NNRTIs has been observed. Cross-resistance to delavirdine, efavirenz, and/or nevirapine is expected after virologic failure with an etravirine-containing regimen. Virologic failure on a rilpivirine-containing regimen with development of rilpivirine resistance is likely to result in cross-resistance to etravirine (see Treatment-Naïve HIV-1-Infected Subjects in the Phase 3 Trials for EDURANT (rilpivirine) below). Cross-resistance to etravirine has been observed after virologic failure on a doravirine-containing regimen with development of doravirine resistance. Some NNRTI-resistant viruses are susceptible to etravirine, but genotypic and phenotypic testing should guide the use of etravirine (see Baseline Genotype/Phenotype and Virologic Outcome Analyses below).

Site-Directed NNRTI Mutant Virus

Etravirine showed antiviral activity against 55 of 65 HIV-1 strains (85%) with single amino acid substitutions at RT positions associated with NNRTI resistance, including the most commonly found K103N. The single amino acid substitutions associated with an etravirine reduction in susceptibility greater than 3-fold were K101A, K101P, K101Q, E138G, E138Q, Y181C, Y181I, Y181T, Y181V, and M230L, and of these, the greatest reductions were Y181I (13-fold change in EC50 value) and Y181V (17-fold change in EC50 value). Mutant strains containing a single NNRTI resistance-associated substitution (K101P, K101Q, E138Q, or M230L) had cross-resistance between etravirine and efavirenz.

The majority (39 of 61; 64%) of the NNRTI mutant viruses with 2 or 3 amino acid substitutions associated with NNRTI resistance had decreased susceptibility to etravirine (fold-change greater than 3). The highest levels of resistance to etravirine were observed for HIV-1 harboring a combination of substitutions V179F + Y181C (187 fold-change), V179F + Y181I (123 fold-change), or V179F + Y181C + F227C (888 fold-change).

Clinical Isolates

Etravirine retained a fold-change less than or equal to 3 against 60% of 6171 NNRTI-resistant clinical isolates. In the same panel, the proportion of clinical isolates resistant to delavirdine, efavirenz and/or nevirapine (defined as a fold-change above their respective biological cutoff values in the assay) was 79%, 87%, and 95%, respectively. In TMC125-C206 and TMC125-C216, 34% of the baseline isolates had decreased susceptibility to etravirine (fold-change greater than 3) and 60%, 69%, and 78% of all baseline isolates were resistant to delavirdine, efavirenz, and nevirapine, respectively. Of subjects who received etravirine and were virologic failures in TMC125-C206 and TMC125-C216, 90%, 84%, and 96% of viral isolates obtained at the time of treatment failure were resistant to delavirdine, efavirenz, and nevirapine, respectively.

Treatment-Naïve HIV-1-Infected Subjects in the Phase 3 Trials for EDURANT (Rilpivirine)

There are currently no clinical data available on the use of etravirine in subjects who experienced virologic failure on a rilpivirine-containing regimen. However, in the rilpivirine adult clinical development program, there was evidence of phenotypic cross-resistance between rilpivirine and etravirine. In the pooled analyses of the Phase 3 clinical trials for rilpivirine, 38 rilpivirine virologic failure subjects had evidence of HIV-1 strains with genotypic and phenotypic resistance to rilpivirine. Of these subjects, 89% (34 subjects) of virologic failure isolates were cross-resistant to etravirine based on phenotype data. Consequently, it can be inferred that cross-resistance to etravirine is likely after virologic failure and development of rilpivirine resistance. Refer to the prescribing information for EDURANT (rilpivirine) for further information.

Baseline Genotype/Phenotype and Virologic Outcome Analyses

In TMC125-C206 and TMC125-C216, the presence at baseline of the substitutions L100I, E138A, I167V, V179D, V179F, Y181I, Y181V, or G190S was associated with a decreased virologic response to etravirine. Additional substitutions associated with a decreased virologic response to etravirine when in the presence of 3 or more additional 2008 IAS-USA defined NNRTI substitutions include A98G, K101H, K103R, V106I, V179T, and Y181C. The presence of K103N, which was the most prevalent NNRTI substitution in TMC125-C206 and TMC125-C216 at baseline, did not affect the response in the etravirine arm. Overall, response rates to etravirine decreased as the number of baseline NNRTI substitutions increased (shown as the proportion of subjects achieving viral load less than 50 plasma HIV RNA copies/mL at Week 48) (Table 10).

Table 10: Proportion of Subjects With Less Than 50 HIV-1 RNA Copies/mL at Week 48 by Baseline Number of IAS-USA-Defined NNRTI Substitutions* in the Non-VF Excluded Population of the Pooled TMC125-C206 and TMC125-C216

Response rates assessed by baseline etravirine phenotype are shown in Table 11. These baseline phenotype groups are based on the select subject populations in TMC125-C206 and TMC125-C216 and are not meant to represent definitive clinical susceptibility breakpoints for etravirine. The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to etravirine in treatment-experienced patients.

Table 11: Proportion of Subjects With Less Than 50 HIV-1 RNA Copies/mL at Week 48 by Baseline Phenotype and ENF Use in the Pooled TMC125-C206 and TMC125-C216*

The proportion of virologic responders (viral load less than 50 HIV-1 RNA copies/mL) by the phenotypic susceptibility score (PSS) of the background therapy, including ENF, is shown in Table 12.

Table 12: Virologic Response (Viral Load Less Than 50 HIV-1 RNA Copies/mL) at Week 48 by Phenotypic Susceptibility Score (PSS) in the Non-VF Excluded Population of TMC125-C206 and TMC125-C216

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Etravirine was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to approximately 104 weeks. Daily doses of 50 mg/kg, 200 mg/kg and 400 mg/kg were administered to mice and doses of 70 mg/kg, 200 mg/kg and 600 mg/kg were administered to rats in the initial period of approximately 41 to 52 weeks. The high and middle doses were subsequently adjusted due to tolerability and reduced by 50% in mice and by 50% to 66% in rats to allow for completion of the studies. In the mouse study, statistically significant increases in the incidences of hepatocellular carcinoma and incidences of hepatocellular adenomas or carcinomas combined were observed in treated females. In the rat study, no statistically significant increases in tumor findings were observed in either sex. The relevance of these liver tumor findings in mice to humans is not known. Because of tolerability of the formulation in these rodent studies, maximum systemic drug exposures achieved at the doses tested were lower than those in humans at the clinical dose (400 mg/day), with animal vs. human AUC ratios being 0.6-fold (mice) and 0.2-to-0.7-fold (rats).

Mutagenesis

Etravirine tested negative in the in vitro Ames reverse mutation assay, in vitro chromosomal aberration assay in human lymphocyte, and in vitro clastogenicity mouse lymphoma assay, tested in the absence and presence of a metabolic activation system. Etravirine did not induce chromosomal damage in the in vivo micronucleus test in mice.

Impairment of Fertility

No effects on fertility and early embryonic development were observed when etravirine was tested in rats at maternal doses up to 500 mg/day, resulting in systemic drug exposure up to the recommended human dose (400 mg/day).

14.1 Treatment-Experienced Adult Subjects

The clinical efficacy of etravirine is derived from the analyses of 48-week data from 2 ongoing, randomized, double-blinded, placebo-controlled, Phase 3 trials, TMC125-C206 and TMC125-C216 (DUET-1 and DUET-2) in subjects with 1 or more NNRTI resistance-associated substitutions. These trials are identical in design and the results below are pooled data from the two trials.

TMC125-C206 and TMC125-C216 are Phase 3 studies designed to evaluate the safety and antiretroviral activity of etravirine in combination with a background regimen (BR) as compared to placebo in combination with a BR. Eligible subjects were treatment-experienced HIV-1-infected subjects with plasma HIV-1 RNA greater than 5,000 copies/mL while on an antiretroviral regimen for at least 8 weeks. In addition, subjects had 1 or more NNRTI resistance-associated substitutions at screening or from prior genotypic analysis, and 3 or more of the following primary PI substitutions at screening: D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, V82A/F/L/S/T, I84V, N88S, or L90M. Randomization was stratified by the intended use of ENF in the BR, previous use of darunavir/ritonavir, and screening viral load. Virologic response was defined as HIV-1 RNA less than 50 copies/mL at Week 48.

All study subjects received darunavir/ritonavir as part of their BR, and at least 2 other investigator-selected antiretroviral drugs (N[t]RTIs with or without ENF). Of etravirine-treated subjects, 25.5% used ENF for the first time (de novo) and 20.0% re-used ENF. Of placebo-treated subjects, 26.5% used de novo ENF and 20.4% re-used ENF.

In the pooled analysis for TMC125-C206 and TMC125-C216, demographics and baseline characteristics were balanced between the etravirine arm and the placebo arm (Table 13). Table 13 displays selected demographic and baseline disease characteristics of the subjects in the etravirine and placebo arms.

Table 13: Demographic and Baseline Disease Characteristics of Subjects (Pooled Analysis TMC125-C206 and TMC125-C216)—

Efficacy at Week 48 for subjects in the etravirine and placebo arms for the pooled TMC125-C206 and TMC125-C216 study populations are shown in Table 14.

Table 14: Treatment Outcomes at Week 48 (Pooled Analysis TMC125-C206 and TMC125-C216)

At Week 48, 70.8% of etravirine-treated subjects achieved HIV-1 RNA less than 400 copies/mL as compared to 46.4% of placebo-treated subjects. The mean decrease in plasma HIV-1 RNA from baseline to Week 48 was -2.23 log10 copies/mL for etravirine-treated subjects and -1.46 log10 copies/mL for placebo-treated subjects. The mean CD4+ cell count increase from baseline for etravirine-treated subjects was 96 cells/mm3 and 68 cells/mm3 for placebo-treated subjects.

Of the study population who either re-used or did not use ENF, 57.4% of etravirine-treated subjects and 31.7% of placebo-treated subjects achieved HIV-1 RNA less than 50 copies/mL. Of the study population using ENF de novo, 67.3% of etravirine-treated subjects and 57.2% of placebo-treated subjects achieved HIV-1 RNA less than 50 copies/mL.

Treatment-emergent CDC category C events occurred in 4% of etravirine-treated subjects and 8.4% of placebo-treated subjects.

Study TMC125-C227 was a randomized, exploratory, active-controlled, open-label, Phase 2b trial. Eligible subjects were treatment-experienced, PI-naïve HIV-1-infected subjects with genotypic evidence of NNRTI resistance at screening or from prior genotypic analysis. The virologic response was evaluated in 116 subjects who were randomized to etravirine (59 subjects) or an investigator-selected PI (57 subjects), each given with 2 investigator-selected N(t)RTIs. Etravirine-treated subjects had lower antiviral responses associated with reduced susceptibility to the N(t)RTIs and to etravirine as compared to the control PI-treated subjects.

14.2 Treatment-Experienced Pediatric Subjects (6 Years to Less Than 18 Years of Age)

The efficacy of etravirine for treatment-experienced pediatric subjects is based on one Phase 2 trial, TMC125-C213.

Pediatric Subjects (6 Years to Less Than 18 Years of Age [TMC125-C213])

TMC125-C213, a single-arm, Phase 2 trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of etravirine enrolled 101 antiretroviral treatment-experienced HIV-1 infected pediatric subjects 6 years to less than 18 years of age and weighing at least 16 kg. Subjects eligible for this trial were on an antiretroviral regimen with confirmed plasma HIV-1 RNA of at least 500 copies/mL and viral susceptibility to etravirine at screening.

The median baseline plasma HIV-1 RNA was 3.9 log10 copies/mL, and the median baseline CD4+ cell count was 385 x 106 cells/mm3.

At Week 24, 52% of subjects had HIV-1 RNA less than 50 copies per mL. The proportion of subjects with HIV-1 RNA less than 400 copies/mL was 67%. The mean CD4+ cell count increase from baseline was 112 x 106 cells/mm3.

Additional pediatric use information is approved for Janssen Products, LP’s INTELENCE® (etravirine) tablets. However, due to Janssen Products, LP’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.